Detection, monitoring and treatment of cancer
Abstract
There are disclosed aptamer ligands to MUC1, preferably comprising a sequence selected from: <tables id="TABLE-US-00001" num="1"> <table frame="none" colsep="0" rowsep="0" tabstyle="monospace"> <tgroup align="left" colsep="0" rowsep="0" cols="4"> <colspec colname="OFFSET" colwidth="35PT" align="left"/> <colspec colname="1" colwidth="42PT" align="left"/> <colspec colname="2" colwidth="140PT" align="left"/> <colspec colname="3" colwidth="0PT" align="left"/> <TBODY VALIGN="TOP"> <ROW> <ENTRY/> <ENTRY/> </ROW> <ROW> <ENTRY/> <ENTRY> 1</ENTRY> <ENTRY>CGAATGGGCCCGTCCTCGCTGTAAG</ENTRY> <ENTRY/> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> 2</ENTRY> <ENTRY>GCAACAGGGTATCCAAAGGATCAAA</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> 3</ENTRY> <ENTRY>GTTCGACAGGAGGCTCACAACAGGC</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> 4</ENTRY> <ENTRY>TGTTGGTCAGGCGGCGGCTCTACAT</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> 5</ENTRY> <ENTRY>CTCTGTTCTTATTTGCGAGTTXXXX</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> 6</ENTRY> <ENTRY>XCTCTGTTCTTATTTGCGAGTTXXX</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> 7</ENTRY> <ENTRY>XXCTCTGTTCTTATTTGCGAGTTXX</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> 8</ENTRY> <ENTRY>XXXCTCTGTTCTTATTTGCGAGTTX</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> 9</ENTRY> <ENTRY>XXXXCTCTGTTCTTATTTGCGAGTT</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>10</ENTRY> <ENTRY>CTCTGTTCTTATTTGCGAGTT</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>11</ENTRY> <ENTRY>CCCTCTGTTCTTATTTGCGAGTTCA</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>12</ENTRY> <ENTRY>CTCTGTTCTTATTTGCGAGTTGGTG</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>13</ENTRY> <ENTRY>CCCTCTGTTCTTATTTGCGAGTTCA</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>14</ENTRY> <ENTRY>TAAGAACAGGGCGTCGTGTTACGAG</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>15</ENTRY> <ENTRY>GTGGCTTACTGCGAGGACGGGCCCA</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>16</ENTRY> <ENTRY>GCAGTTGATCCTTTGGATACCCTGG</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>17</ENTRY> <ENTRY>AACCCTATCCACTTTTCGGCTCGGG</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>18</ENTRY> <ENTRY>CGATTTAGTCTCTGTCTCTAGGGGT</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>19</ENTRY> <ENTRY>CGACAGGAGGCTCACAACAGGCAAC</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>20</ENTRY> <ENTRY>AGAACGAAGCGTTCGACAGGAGGCT</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>21</ENTRY> <ENTRY>AGAAACACTTGGTATATCGCAGATA</ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY> </ENTRY> </ROW> <ROW> <ENTRY/> <ENTRY>22</ENTRY> <ENTRY>GGGAGACAAGAATAAACACTCAACG</ENTRY> </ROW> </TBODY> </TGROUP> </TABLE> </TABLES> and compounds comprising these aptamers and sequences. There are also disclosed compounds having the structure formula (I) and (II). There are also disclosed methods of treatment, diagnosis, detection and imaging using these compounds, their use in such methods, and their use in the preparation of medicaments and products for such methods.
Claims
exact text as granted — not AI-modified1 . An aptamer ligand to MUC1.
2 . An aptamer ligand according to claim 1 wherein the aptamer is a DNA/RNA oligonucleotide comprising natural, modified and/or unnatural nucleotides.
3 . An aptamer comprising a sequence selected from:
(SEQ ID NO.:1)
CGAATGGGCCCGTCCTCGCTGTAAG
(SEQ ID NO.:2)
GCAACAGGGTATCCAAAGGATCAAA
(SEQ ID NO.:3)
GTTCGACAGGAGGCTCACAACAGGC
(SEQ ID NO.:4)
TGTTGGTCAGGCGGCGGCTCTACAT
(SEQ ID NO.:5)
CTCTGTTCTTATTTGCGAGTTXXXX
(SEQ ID NO.:6)
XCTCTGTTCTTATTTGCGAGTTXXX
(SEQ ID NO.:7)
XXCTCTGTTCTTATTTGCGAGTTXX
(SEQ ID NO.:8)
XXXCTCTGTTCTTATTTGCGAGTTX
(SEQ ID NO.:9)
XXXXCTCTGTTCTTATTTGCGAGTT
(SEQ ID NO.:10)
CTCTGTTCTTATTTGCGAGTT
(SEQ ID NO.:11)
CCCTCTGTTCTTATTTGCGAGTTCA
(SEQ ID NO.:12)
CTCTGTTCTTATTTGCGAGTTGGTG
(SEQ ID NO.:13)
CCCTCTGTTCTTATTTGCGAGTTCA
(SEQ ID NO.:14)
TAAGAACAGGGCGTCGTGTTACGAG
(SEQ ID NO.:15)
GTGGCTTACTGCGAGGACGGGCCCA
(SEQ ID NO.:16)
GCAGTTGATCCTTTGGATACCCTGG
(SEQ ID NO.:17)
AACCCTATCCACTTTTCGGCTCGGG
(SEQ ID NO.:18)
CGATTTAGTCTCTGTCTCTAGGGGT
(SEQ ID NO.:19)
CGACAGGAGGCTCACAACAGGCAAC
(SEQ ID NO.:20)
AGAACGAAGCGTTCGACAGGAGGCT
(SEQ ID NO.:21)
AGAAACACTTGGTATATCGCAGATA
(SEQ ID NO.:22)
GGGAGACAAGAATAAACACTCAACG
wherein each X is independently a natural, non-natural, modified or derivatised nucleic acid.
4 . An aptamer according to claim 3 , wherein each X is independently selected from G, C, A, T and U.
5 . An aptamer comprising a sequence substantially homologous to a sequence defined in claim 3 .
6 . An aptamer comprising a sequence which is at least 90% homologous to a sequence defined in claim 3 .
7 . An aptamer comprising a sequence which is at least 80% homologous to a sequence defined in claim 3 .
8 . An aptamer comprising a sequence which is at least 70% homologous to a sequence defined in claim 3 .
9 . An aptamer ligand to MUC1 comprising a tertiary structure substantially the same as the tertiary structure of an aptamer as defined in claim 1 .
10 . An aptamer which has a mode of binding to MUC1 which is substantially the same as that of an aptamer as defined in claim 3 .
11 . An aptamer according to claim 1 comprising a modified and/or non-natural nucleotide.
12 . An aptamer according to claim 1 comprising a modified sugar group.
13 . An aptamer according to claim 12 wherein the modified sugar group has an amino group.
14 . An aptamer according to claim 11 wherein the modified or non-natural nucleotide or group is at the 3′ end of the aptamer.
15 . A compound having the structure:
wherein
R 1 , R 2 , R 3 are each independently: hydrogen, R 4 , R 5 , R 5 -carbonyl, R 5 -sulphonyl;
R 4 comprises an amino acid moiety;
R 5 is: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein each of these groups is optionally substituted by one or more of: alkyl, amino, amino-carbonyl, amino-sulphonyl, halo, cyano, hydroxy, nitro, trifluoromethyl, alkoxy, alkoxycarbonyl, aryl and alkylthio;
and salts and solvates thereof.
16 . A compound according to claim 15 wherein R 4 comprises a lysine, cysteine, glycine, threonine, serine, arginine or methionine moiety.
17 . A compound according to claim 15 wherein R 1 , R 2 and R 3 are hydrogen.
18 . A compound according to claim 15 wherein at least one of R 1 , R 2 and R 3 is alkyl.
19 . A compound according to claim 15 wherein R 4 comprises a carboxyl or amino group.
20 . A compound according to claim 15 wherein R 4 comprises a nitrogen, oxygen or sulphur atom.
21 . A compound according to claim 15 , wherein R 4 has the structure:
22 . A compound according to claim 15 having the structure:
23 . A compound according to claim 1 , further containing a complexing metal (M).
24 . A compound having the structure:
wherein R 1 , R 2 , R 3 are each independently:
hydrogen, R 4 , R 5 , R 5 -carbonyl, R 5 -sulphonyl;
R 4 comprises an amino acid moiety;
R 5 is:
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, wherein each of these groups is optionally substituted by one or more of:
alkyl, amino, amino-carbonyl, amino-sulphonyl, halo, cyano, hydroxy, nitro, trifluoromethyl, alkoxy, alkoxycarbonyl, aryl and alkylthio;
and salts and solvates thereof.
25 . A compound according to claim 24 wherein R 4 comprises a lysine, cysteine, glycine, threonine, serine, arginine or methionine moiety.
26 . A compound according to claim 24 wherein R 1 , R 2 and R 3 are hydrogen.
27 . A compound according to claim 24 wherein at least one of R 1 , R 2 and R 3 is alkyl.
28 . A compound according to claim 24 wherein R 4 comprises a carboxyl or amino group.
29 . A compound according to claim 24 wherein R 4 comprises a nitrogen, oxygen or sulphur atom.
30 . A compound according to claim 24 wherein R 4 has the structure:
31 . A compound according to claim 24 having the structure:
32 . A compound according to claim 23 , wherein M is rhenium, technitium or yttrium.
33 . A compound according to claim 23 , wherein M is a radioisotope.
34 . A compound comprising an aptamer as defined in claim 1 and a non-nucleic acid moiety.
35 . A compound according to claim 34 , wherein the non-nucleic acid moiety comprises a ligand for a metal.
36 . A compound according to claim 34 , wherein the non-nucleic acid moiety comprises a nitrogen-containing ring.
37 . A compound according to claim 34 , wherein the non-nucleic acid moiety comprises a cyclen.
38 . A compound comprising an aptamer ligand to MUC1 and a non-nucleic acid moiety, wherein the non-nucleic acid moiety comprises a compound as defined in claim 15 .
39 . A compound according to claim 34 , wherein the non-nucleic acid moiety comprises a porphyrin.
40 . A compound according to claim 39 wherein the non-nucleic acid moiety comprises the compound having the formula:
41 . A compound according to claim 34 , wherein the non-nucleic acid moiety comprises a sulphur-containing group.
42 . A compound according to claim 34 , wherein the non-nucleic acid moiety comprises the moiety:
43 . A compound according to claim 34 , wherein an amino group of the aptamer is connected to a carboxyl group of the non-nucleic acid moiety.
44 . A compound according to claim 43 wherein the amino group of the aptamer is located on a sugar.
45 . A compound according to claim 34 wherein the aptamer is connected to the non-nucleic acid moiety by a spacer.
46 . A compound according to claim 45 wherein the spacer is selected from phosphoramidite 9, phosphoramidite C3, dSpacer CE phosphoramidite, spacer phosphoramidite 18, spacer C12 CE phosphoramidite, 3′ spacer CE.
47 . A compound according to claim 45 wherein the spacer is a peptide moiety.
48 . A compound according to claim 34 , wherein the non-nucleic acid moiety has therapeutic activity.
49 . A compound according to claim 34 , wherein the non-nucleic acid moiety has diagnostic activity.
50 . A compound according to claim 34 , wherein the non-nucleic acid moiety is remotely detectable.
51 . A compound comprising an aptamer as defined in claim 1 , a non-nucleic acid moiety and a complexing metal (M).
52 . A compound according to claim 51 , wherein the non-nucleic acid moiety comprises a ligand for a metal.
53 . A compound according to claim 51 , wherein the non-nucleic acid moiety comprises a nitrogen-containing ring.
54 . A compound according to claim 51 , wherein the non-nucleic acid moiety comprises a cyclen.
55 . A compound comprising an aptamer ligand to MUC1, a non-nucleic acid moiety, and a complexing metal (M), wherein the non-nucleic acid moiety comprises a compound as defined in claim 15 .
56 . A compound according to claim 51 , wherein the non-nucleic acid moiety comprises a porphyrin.
57 . A compound according to claim 56 wherein the non-nucleic acid moiety comprises the compound having the structure:
58 . A compound according to claim 51 , wherein the non-nucleic acid moiety comprises a sulphur-containing group.
59 . A compound according to claim 51 , wherein the non-nucleic acid moiety comprises the moiety:
60 . A compound according to claim 51 , wherein an amino group of the aptamer is connected to a carboxyl group of the non-nucleic acid moiety.
61 . A compound according to claim 60 wherein the amino group of the aptamer is located on a sugar.
62 . A compound according to claim 51 wherein the aptamer is connected to the non-nucleic acid moiety by a spacer.
63 . A compound according to claim 62 wherein the spacer is selected from phosphoramidite 9, phosphoramidite C3, dSpacer CE phosphoramidite, spacer phosphoramidite 18, spacer C12 CE phosphoramidite, 3′ spacer CE.
64 . A compound according to claim 62 wherein the spacer is a peptide moiety.
65 . A compound according to claim 51 , wherein M is rhenium, technitium or yttrium.
66 . A compound according to claim 51 , wherein M is a radioisotope.
67 . A compound according to claim 51 , wherein the non-nucleic acid moiety has therapeutic activity.
68 . A compound according to claim 51 , wherein the non-nucleic acid moiety has diagnostic activity.
69 . A compound according to claim 51 , wherein the non-nucleic acid moiety is remotely detectable.
70 . A compound according to claim 51 , wherein the non-nucleic acid moiety has imaging properties.
71 . A pharmaceutical composition comprising a compound or aptamer as defined in claim 1 and a pharmaceutically acceptable carrier.
72 . A method of preventing and/or treating a disease or condition comprising the step of administering a compound, aptamer or pharmaceutical composition as defined in claim 1 to a subject.
73 . A method according to claim 72 , wherein the disease or condition is associated with the over-production of MUC1.
74 . A method according to claim 72 , wherein the disease or condition is selected from cancer, cystic fibrosis, asthma, chronic obstructive lung disease, non-malignant inflammatory epithelial disease, adenocarcinoma, breast cancer, colon cancer, pancreatic cancer, lung adenocarcinoma, non-small cell lung cancer, ovarian cancer, stomach cancer, prostate cancer, endometrium cancer and colorectal cancer.
75 . A method according to claim 72 , wherein MUC1 bearing and/or expressing cells are irradiated by the compound, aptamer or pharmaceutical composition.
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